The results summarized below were obtained in collaborative studies. M4 muscarinic receptors as potential targets for the treatment of schizophrenia Recent work suggests that muscarinic receptors represent a promising new therapeutic target for the treatment of schizophrenia. The molecular mechanisms through which certain muscarinic ligands exert their antipsychotic actions are not well understood. In collaboration with Dr. Jeff Conn's lab, we demonstrated that activation of M4 receptors on medium spiny neurons results in a sustained depression of striatal dopamine release. We also found that the M4 receptor-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy in reversing disrupted pre-pulse inhibition require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism through which striatal cholinergic and cannabinoid signaling inhibits dopaminergic transmission associated with behavioral effects predictive of antipsychotic efficacy. (Foster DJ, Wilson JM, Remke DH, Mahmood MS, Uddin MJ, Wess J, Patel S, Marnett LJ, Niswender CM, Jones CK, Xiang Z, Lindsley CW, Rook JM, Conn PJ. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release. Neuron. 2016 Sep 21;91(6):1244-52) M1 muscarinic receptors as a potential novel target for the treatment of multiple sclerosis Multiple sclerosis (MS) is characterized by demyelination, resulting in the disruption of nerve signals and contributing to axon degeneration. Using a mouse model of MS, we demonstrated that oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, promotes remyelination, preventing axonal loss and improving functional recovery. This finding supports the concept that the M1 receptor represents a potential novel target for the treatment of MS. (Mei F, Lehmann-Horn K, Shen YA, Rankin KA, Stebbins KJ, Lorrain DS, Pekarek K, A Sagan S, Xiao L, Teuscher C, von Bdingen HC, Wess J, Lawrence JJ, Green AJ, Fancy SP, Zamvil SS, Chan JR. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife. 2016 Sep 27;5. pii: e18246. doi: 10.7554/eLife.18246) Role of M1 and M3 muscarinic receptors in in memory retrieval In this study, we examined the role of hippocampal and cortical muscarinic acetylcholine receptors (mAChRs) in memory retrieval. Using pharmacological and genetic approaches, we found that memory formation requires both hippocampal and retrosplenial cortex M1 and M3 receptors. We also demonstrated that co-activation of multiple mAChRs is required for retrieval of both recently and remotely acquired context memories. Our findings indicate that mAChR agonists and/or positive allosteric modulators targeting multiple mAChRs subtypes may have considerable therapeutic potential for the treatment of memory disorders. (Leaderbrand K, Chen HJ, Corcoran KA, Guedea AL, Jovasevic V, Wess J, Radulovic J. Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory. Learn Mem. 2016 Oct 17;23(11):631-638) M1 receptor PAMs as potential novel drugs for the treatment of Alzheimers Disease Mouse prion disease shows many of the hallmarks of human Alzheimers Disease, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. Strikingly, the memory impairments that we observed in mouse prion disease were completely reversed by treatment with compounds that act as selective positive allosteric modulators (PAMs) of the M1 muscarinic receptor (BQZ-12 and BQCA). Moreover, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this class of compounds may prove beneficial in the treatment of Alzheimers Disease. (Bradley SJ, Bourgognon JM, Sanger HE, Verity N, Mogg AJ, White DJ, Butcher AJ, Moreno JA, Molloy C, Macedo-Hatch T, Edwards JM, Wess J, Pawlak R, Read DJ, Sexton PM, Broad LM, Steinert JR, Mallucci GR, Christopoulos A, Felder CC, Tobin AB. M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J Clin Invest. 2017 Feb 1;127(2):487-499) M1 receptor antagonists may prove useful for the treatment of peripheral neuropathy In this study, we found that sensory neurons from M1 muscarinic receptor KO mice showed enhanced neurite outgrowth, indicating that M1 receptors tonically suppress axonal plasticity. Moreover, M1 receptor-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. In agreement with this observation, pharmacological blockade of M1 receptors prevented or reversed peripheral neuropathy in mice. These novel findings suggest that selective M1 receptor antagonists may prove useful for the treatment of peripheral neuropathy. (Calcutt NA, Smith DR, Frizzi K, Sabbir MG, Chowdhury SK, Mixcoatl-Zecuatl T, Saleh A, Muttalib N, Van der Ploeg R, Ochoa J, Gopaul A, Tessler L, Wess J, Jolivalt CG, Fernyhough P. Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. J Clin Invest. 2017 Feb 1;127(2):608-622) M4 receptor PAMs promote cognition and exert antipsychotic effects We evaluated the effects of a highly selective M4 receptor positive allosteric modulator (PAM; VU0467154) on acquisition and/or consolidation of learning and memory. In wildtype mice, but not M4 receptor KO mice, chronic administration of the M4 PAM significantly enhanced the rate of learning in various cognitive tasks. Moreover, chronic treatment with the M4 PAM resulted in antipsychotic activity in two mouse models of psychosis. These findings strongly support the concept that M4 receptor PAMs many prove clinically useful for the treatment of cognitive deficits and psychosis. (Gould RW, Grannan MD, Gunter BW, Ball J, Bubser M, Bridges TM, Wess J, Wood MW, Brandon NJ, Duggan ME, Niswender CM, Lindsley CW, Conn PJ, Jones CK. Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154. Neuropharmacology. 2017 Jul 17. pii: S0028-3908(17)30343-X. doi: 10.1016/j.neuropharm.2017.07.013, Epub ahead of print)